Parkinson's disease (PD) is a progressive neurodegenerative disease that follows an insidious, protracted time-course during the initiation and early progression phases (neurodegenerative cascade). Although this delayed time-course presents increased diagnostic and therapeutic challenges for the high-risk population, it also provides a window of opportunity for an early prophylactic intervention. Mechanisms underlying the progression of PD have not fully elucidated, however, recent studies have implicated, among others, a cascade involving microglia (and astrocyte) activation and subsequent increase in oxidative stress via induction of the inducible form of nitric oxide synthase (iNOS). One of the main hypotheses for this proposal is that the success of preventive intervention would critically depend not only on elucidating underlying causes (e.g., oxidative stress) but also delineating various dynamic, compensatory changes that may occur in the nigrostriatal (N-ST) dopamine (DA) neurons during the early time period. Using a rat model of progressive N-ST degeneration (partial 6-OHDA lesion in the caudate/putamen (CD/PTM)) and real-time electrophysiological and voltametric techniques, we will first characterize the early N-ST changes in neuronal activity and DA release/uptake dynamics during the first 10 days following a striatal 6-OHDA injection. Specific mechanisms to be tested include soma/dendritic and terminal DA autoreceptors, NMDA receptors basic neuronal membrane properties, and NO regulation; selective pharmacological agents and oligodeoxynucleotide antisenses will be used. Subsequently, these data will guide us in evaluating standard and experimental pharmacotherapies in preventing/reversing the electrophysiological and voltametric alterations in the N-ST DA system. It is expected that systematic delineation of the ongoing pathological process and regulatory changes in the N-ST DA neurons would facilitate formulation of treatment strategies.